Effects of GYKI 52466 and CNQX, AMPA/kainate receptor antagonists, on the micturition reflex in the rat

doi:10.1016/0006-8993(95)00671-C

Brain Research

Volume 691, Issues 1–2, 11 September 1995, Pages 185-194

https://doi.org/10.1016/0006-8993(95)00671-C Get rights and content

Abstract

GYKI 52466, a non-competitive AMPA/kainate glutamate receptor antagonist, administered in graded doses (0.5–8 mg/kg, i.v.) at 10 min intervals, decreased the amplitude and duration of reflex bladder contractions (maximal inhibition = 63%), the intercontraction interval (maximal inhibition = 83%) and external urethral spincter activity (maximal inhibition = 91%) in urethane-anesthetized (1.2 g/kg, s.c.) intact rats during continuous transurethral cystometrograms. On the other hand, in unanesthetized decebrate rats, the drug did not alter reflex bladder activity but did produce a significant depression of sphincter activity (maximal inhibition = 59%). The depressant effects of single doses of GYKI 52466 (4 mg/kg, i.v.) on external urethral sphincter EMG activity occurred with similar time courses in both urethane-anesthetized (1.2 g/kg, s.c.) intact and unanesthetized decerebrate rats during continuous transurethral cystometrograms. In urethane-treated (0.6 g/kg, i.p.) decerebrate rats, GYKI 52466 (0.5-4 mg/kg, i.v.) depressed bladder contraction amplitude and sphincter EMG activity, similar to the effects in urethane-anesthetized (1.2 g/kg, s.c.) intact rats. CNQX (0.01-1 mg/kg, i.v.), a competitive AMPA/kainate receptor antagonists, administered to urethane-anesthetized (1.2 g/kg. s.c.) intact or unanesthetized decerebrate rats did not alter the bladder or the external urethral sphincter activity during continuous transurethral cystometrograms, possibly due to the inability of the drug to readily cross the blood-brain barrier. The present results indicate that glutamatergic excitatory transmission mediated by AMPA/kainate receptors is essential for the activation of external urethral sphincter activity during micturition in anesthetized and unanesthetized preparation. However, the depressant effect of GYKI 52466 on reflex bladder activity is only unmasked by urethane anesthesia, raising the possibility that urethane interacts with AMPA/kainate glutamate receptors in the spinobulbospinal micturition reflex pathway.

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Citation Excerpt :
In contrast, Yoshiyama and de Groat (2001) reported that intrathecal injection of a selective α1A-AR antagonist, RS-100329, increased the frequency of bladder contractions in anesthetized rats, indicating that α1A-AR activation inhibits the spinal processing of afferent input from the urinary bladder. Overall, apparent contradictory actions of α1-AR blockers have been documented, but these differences may have been due to the depth of anesthesia, as anesthesia affects glutamatergic signaling in the control of the micturition reflex (Yoshiyama et al., 1994, 1995). In the present study, intrathecal application of terazosin, a non-selective α1-AR blocker, inhibited C-fiber dependent NVCs without affecting the voiding pressure in conscious SCI rats.
To confirm the role of alpha1-adrenoceptor (α₁-AR) in the spinal cord, we investigated the effect of intrathecal application of terazosin, a non-selective α₁-AR blocker, on the micturition reflex, as well as the change of α₁-AR subtypes mRNA in the lumbosacral spinal cord using spinal cord injury (SCI) rats.
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1) Terazosin (0.01–10 μg) inhibited the number of non-voiding bladder contractions, and increased bladder capacity by 73%. 2) Phenylephrine (0.1 mg/kg) reduced bladder capacity by 17%, and voiding efficiency by 20%. Intrathecal terazosin blocked the effect of intravenous phenylephrine. 3) α₁-AR subtype mRNA levels was all increased after SCI.
These results suggest that α₁-AR facilitates the micturition reflex in the spinal cord, and α₁-AR blockers applied in the lumbosacral spinal inhibits this effect. Upregulation of α₁-AR in the lumbosacral spinal cord could be involved in the genesis of detrusor overactivity after SCI. Therefore, if α₁-AR blockers pass the blood–brain barrier, they could act in the spinal cord to improve storage function in patients with detrusor overactivity (DO).
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Effects of tacrolimus, a protein phosphatase 2B inhibitor, on the reflex plasticity between the pelvic afferent nerve fibers and the urethra were examined in urethane-anesthetized rats. Repetitive stimulation (1Hz) induced a potentiation (0.9±0.2 and 10.5±1.6 spikes in control and repetitive stimulation groups, respectively, P<0.01, N=10) in the activities of the pelvic-urethral reflex. Intrathecal tacrolimus (0.1mM, 10μl, bolus) blocked repetitive stimulation-induced potentiation in pelvic-urethral reflex activities (3.2±0.9 spikes in tacrolimus group versus 10.5±1.6 spikes in repetitive stimulation group, P<0.01, N=10). Glutamate (intrathecal, 0.1mM, 10μl, bolus) and N-methyl-d-aspartic acid (intrathecal, 0.1mM, 10μl, bolus) both reversed the blocking effects exerted by tacrolimus on repetitive stimulation-induced pelvic-urethral reflex potentiation (15.0±1.4 spikes in glutamate group and 11.4±1.4 spikes in N-methyl-d-aspartic acid group versus 3.2±0.9 spikes in tacrolimus-treated repetitive stimulation group, P<0.01, N=7). In addition, the reversal effect elicited by these two agonists of glutamate receptors showed no statistical difference (P=NS, N=7). All these results demonstrated that tacrolimus could block glutamatergic N-methyl-d-aspartic acid receptor-mediated potentiation in pelvic-urethral reflex activities. This finding may be pathologically relevant in patients who take tacrolimus as immunosuppressant therapy. Whether tacrolimus will induce urine incontinence in such patients or not needs further investigation.
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We induced radio frequency (RF) lesions in the neuronal pathway leading from the forebrain to the pontine micturition center (PMC) to produce a rat model of bladder overactivity. We studied the effects of γ-aminobutyric acid agonists (diazepam and baclofen) and glutamate receptor antagonists (MK-801 maleate and GYKI52466 [1-(4-aminophenyl-D-4-methyl-7,8 methylenedioxy-5H-2,3-benzodiazepine] hydrochloride) on the cystometrogram and developed a possible explanation of the neuronal mechanisms underlying RF lesion induced bladder overactivity.
Seven-week-old male Sprague-Dawley rats were anesthetized with sodium pentobarbital and RF lesions were produced in the nuclei basalis. Five days later bladder contractions were induced by infusing fluid into the bladder and cystometrograms were measured in conscious rats.
The micturition interval (MI) in rats subjected to RF lesioning was significantly shorter than that in sham operated control rats. Diazepam (0.1 and 1 mg/kg intraperitoneally), baclofen (1 mg/kg intravenously) and MK-801 (0.1 and 1 mg/kg intravenously) did not change or shortened MI in control rats but it prolonged MI in lesioned rats. GYKI52466 (0.5 and 1 mg/kg intravenously) weakly prolonged MI in lesioned rats.
We consider that RF lesioning causes interruption of the inhibitory GABAergic neurons that lead from the forebrain to the PMC. This results in the activation of N-methyl-D-aspartate receptors in the PMC that are involved in the facilitation of voiding.
Supraspinal and spinal α-amino-3-hydroxy-5-methylisoxazole-4- propionic acid and N-methyl-D-aspartate glutamatergic control of the micturition reflex in the urethane-anesthetized rat
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Effects of i.c.v. and i.t. administration of (3SR,4aRS,6RS,8aRS)-6-[2-(1H-tetrazol-5-yl)ethyl]decahydroisoquinoline-3-carboxylic acid (LY215490), a competitive α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist and MK-801, a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist on the micturition reflex were evaluated in urethane-anesthetized rats, to determine if glutamatergic mechanisms in brain as well as spinal cord are important for the control of micturition. I.c.v. or i.t. injection of LY215490 in low doses (0.01–0.03 μg) did not change rhythmic bladder or external urethral sphincter (EUS) electromyogram (EMG) activity during continuous cystometrograms (CMGs; 0.21 ml/min), whereas higher doses (0.1–1 μg) markedly suppressed these responses. During single CMGs (0.04 ml/min), 0.1–1 μg i.c.v. or 0.1–10 μg i.t. doses increased volume threshold and pressure threshold for inducing micturition, and decreased bladder contraction amplitude and voiding efficiency. MK-801 in low doses (0.6 μg i.c.v. or 0.6–1.8 μg for i.t.) did not change bladder contraction amplitude or EUS EMG activity during continuous CMGs, whereas higher doses 6–60 μg markedly suppressed these responses. During single CMGs, MK-801 (6–60 μg i.c.v. or 60 μg i.t.) increased volume threshold and pressure threshold, and decreased voiding efficiency and bladder contraction amplitude. Pretreatment i.c.v. with MK-801 in a dose 1.8 μg which alone had little effect on bladder contraction amplitude and EUS EMG activity, markedly enhanced depressant effects of LY215490 (0.03 μg i.c.v.) on these responses. Administration of same doses of drugs by i.t. route did not elicit a similar synergistic interaction. These data indicate that in urethane-anesthetized rats glutamatergic mechanisms in brain and spinal cord are essential for controlling micturition and that interactions between AMPA and NMDA glutamatergic transmission are important at supraspinal but not spinal sites.
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A non-N-methyl-d-aspartate (non-NMDA) receptor antagonist, 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX), administered intracerebroventricularly (0.1–0.5 μg), significantly inhibited the immobilization stress-induced plasma corticosterone levels in a dose-dependent manner. However, CNQX administered intraperitoneally (1–10 mg/kg) showed a dose-dependent increase of basal plasma corticosterone levels in nonstressed mice and an additive increase of plasma corticosterone levels at the dose of 10 mg/kg in 1 h immobilization-stressed mice. The results suggest that the central and peripheral non-NMDA receptors may be differently involved in the regulation of plasma corticosterone levels in non- and immobilization-stressed mice.
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We investigated the effects of the adrenergic a₂-receptor agonists clonidine, oxymetazoline and tizanidine on bladder contractions induced by infusing fluid into the bladders of conscious male rats. I.v. clonidine and oxymetazoline (both 0.01 to 0.1 mg/kg) caused bladder hyperactivity, expressed by shortening of the intercontraction interval. Tizanidine (0.1 mg/kg, i.v.) caused slight shortening of the intercontraction interval. The rank order of potency was clonidine = oxymetazoline »tizanidine. Intrathecal (i.t.) injection of 10 μg clonidine and oxymetazoline, and intracerebroventricular (i.c.v) injection at 15 #x03BC;g, produced almost the same pattern of bladder hyperactivity as that observed after i.v. injection of these drugs (0.03 mg/kg, i.v.). For all three administration routes of clonidine and oxymetazoline, i.v. idazoxan (0.3 mg/kg) exerted an inhibitory effect on the bladder hyperactivity induced by these drugs, except i.c.v injection of oxymetazoline. I.t. phenylephrine (30 μg) did not change the intercontraction interval. Although i.c.v. phenylephrine (15 μg) shortened the intercontraction interval, the potency was weaker than those of i.c.v. clonidine and oxymetazoline (15 μg). These results suggest that clonidine and oxymetazoline cause bladder hyperactivity by acting at adrenergic α2 receptors in the micturition centers of the lumbosacral and supraspinal regions.

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Research reportEffects of GYKI 52466 and CNQX, AMPA/kainate receptor antagonists, on the micturition reflex in the rat

Abstract

Brain Res.

Eur. J. Pharmacol.

Neurosci. Lett.

Brain Res.

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Brain Res. Bull.

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Eur. J. Pharmacol.

Neurosci. Lett.

Eur. J. Pharmacol.

Neurosci. Lett.

Research report
Effects of GYKI 52466 and CNQX, AMPA/kainate receptor antagonists, on the micturition reflex in the rat